Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., inducing differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, life support action, and the like. It has also been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. 61-22047 and 61-76440, the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p. 2182, and the like. Retinoic acid and compounds having retinoic acid-like biological activities are collectively referred to as “retinoids”.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cellular nucleus, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p. 889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities (Petkovich, M., et al., Nature, 330, pp. 444-450, 1987). In addition, as for expression of physiological activities of retinoic acid, the existence of retinoid X receptor (RXR, of which ligand is 9-cis-retinoic acid) has been elucidated. The retinoid X receptor has been revealed to control the expression of the activities of retinoic acid by forming a dimer with the retinoic acid receptor (RAR) to induce or suppress transcription of a target gene (Mangelsdorf, D. J. et al., Nature, 345, pp. 224-229).
It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities (e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80), etc.) also bind to RAR in similar manners to that of retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990). These compounds were found to be clinically useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia and certain types of cancer. For example, Am80 is clinically used as a therapeutic agent for recurrent leukaemia, and 4-[3,5-bis-(trimethylsilyl)benzamido]benzoic acid (Am555S, Japanese Patent Unexamined Publication No. 2-247185, etc.) is under the clinical development in the United States as an orally administrable antitumor agent.
As described above, retinoids are used as therapeutic agents for cancers, dermatological agents, and the like, and also have significant possibility as therapeutic agents for other various intractable diseases. However, the currently used retinoids are not fully satisfactory from viewpoints of side reactions and the like, and improvements have been desired in enhancement of selectivity for target organ and reduction of organopathy induced by acidic groups, as well as relief of direct actions on the alimentary canal especially in the case of oral administration, and the like. The latter problem may possibly be solved by providing a retinoid prodrug compound having a property of being converted into a retinoid after absorption in vivo. However, almost no compounds have been proposed so far from the above viewpoint.    Patent document 1: Japanese Patent Unexamined Publication No. 61-22047    Patent document 2: Japanese Patent Unexamined Publication No. 61-76440    Patent document 3: Japanese Patent Unexamined Publication No. 2-247185    Non-patent document 1: Journal of Medicinal Chemistry, 31, No. 11, p. 2182, 1988    Non-patent document 2: Cell struct. Funct., 16, pp. 113-123, 1991    Non-patent document 3: Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990